TY - JOUR T1 - Dehydroalanine Analog of Glutathione: An Electrophilic Busulfan Metabolite That Binds to Human Glutathione <em>S</em>-Transferase A1-1 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 770 LP - 776 DO - 10.1124/jpet.108.142208 VL - 327 IS - 3 AU - Islam R. Younis AU - Meenal Elliott AU - Cody J. Peer AU - Arthur J. L. Cooper AU - John T. Pinto AU - Gregory W. Konat AU - Michal Kraszpulski AU - William P. Petros AU - Patrick S. Callery Y1 - 2008/12/01 UR - http://jpet.aspetjournals.org/content/327/3/770.abstract N2 - Elimination of hydrogen sulfide from glutathione (GSH) converts a well known cellular nucleophile to an electrophilic species, γ-glutamyldehydroalanylglycine (EdAG). We have found that a sulfonium metabolite formed from GSH and busulfan undergoes a facile β-elimination reaction to give EdAG, which is an α,β-unsaturated dehydroalanyl analog of GSH. EdAG was identified as a metabolite of busulfan in a human liver cytosol fraction. EdAG condenses with GSH in a Michael addition reaction to produce a lanthionine thioether [(2-amino-5-[[3-[2-[[4-amino-5-hydroxy-5-oxopentanoyl]amino]-3-(carboxymethylamino)-3-oxopropyl]sulfanyl-1-(carboxymethylamino)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid); GSG], which is a nonreducible analog of glutathione disulfide. EdAG was less cytotoxic than busulfan to C6 rat glioma cells. GSH and EdAG were equally effective in displacing a glutathione S-transferase (GST) isozyme (human GSTA1-1) from a GSH-agarose column. The finding of an electrophilic metabolite of GSH suggests that alteration of cellular GSH concentrations, irreversible nonreducible glutathionylation of proteins, and interference with GST function may contribute to the toxicity of busulfan. The American Society for Pharmacology and Experimental Therapeutics ER -